July 29, 2007 -- Twenty-one years after they first described a fatal genetic disorder in Missouri and Arkansas families, scientists at Washington University School of Medicine in St. Louis have linked the condition to mutations in a gene known as TREX1.

The study appears online in Nature Genetics.

The identification will accelerate efforts to understand and treat retinal vasculopathy with cerebral leukodystrophy (RVCL), a rare condition that usually goes unrecognized or is misdiagnosed. In Asian and Caucasian patients with the disease, a complex and ultimately fatal barrage of primarily central nervous system symptoms begins around age 45 that includes vision loss, mini-strokes and dementia. The symptoms can also mimic a brain tumor or multiple sclerosis. After onset, RVCL is fatal in 10 years or less.

Because small blood vessels in the back of the eye and the brain disappear in patients with RVCL, the new link could have important relevance to a much broader range of health problems affecting the elderly, including common diseases like diabetes that also alter microvessels.

"Why TREX1 mutations would suddenly cause these blood vessels to start disappearing at midlife is a mystery," says senior author John Atkinson, M.D., the Samuel Grant Professor of Medicine and professor of molecular microbiology. "But now that we have this link, what it teaches us about the health and maintenance of these blood vessels also may help a great deal in understanding and preventing their loss in aging and in diabetes."

Also on the list of disorders linked to blood vessel loss is vascular dementia, a condition that causes memory loss, disorientation, and emotional problems in the elderly. In the United States, vascular dementia is the second-leading cause of these kinds of symptoms after Alzheimer's disease; in some Asian nations, it is the leading cause of dementia.

Gil Grand, M.D., professor of clinical ophthalmology and visual sciences at Washington University, and Atkinson led the research team that in 1986 first reported RVCL as a novel human disease. Since then, researchers have identified other families with RVCL in Europe, Australia and Taiwan.

In 2002, Atkinson's group and colleagues at other institutions tied the condition to a portion of the third chromosome. Unfortunately, the region is rich with more than 150 complex genes, and initial attempts to locate the specific gene that causes RVCL were unsuccessful.

With a grant from the School of Medicine at Washington University, scientists recently began a new attempt. The lead researcher, Anna Richards, M.D., Ph.D., at that time a member of the Atkinson lab and now clinical lecturer in nephrology, Royal Infirmary, Edinburgh, elected to begin the search with a simple gene whose structure made it easiest to sequence.

In a stroke of good fortune, that gene, TREX1, turned out to be the gene they were looking for. In the 10 families scientists studied, they found that family members with RVCL consistently had one of five different TREX1 mutations.

A small but rapidly expanding body of scientific literature already exists on TREX1, which is an important mammalian gene. It is active in almost all cells, where it proofreads DNA for errors and helps correct those mistakes. Cells sometimes introduce such errors into DNA when they copy it prior to cell division, and environmental factors like radiation and reactive chemicals can also create errors.

According to Atkinson, though, there's little in the limited TREX1 literature to suggest why mutations in the gene should cause small blood vessels to start dying off in middle-aged RVCL patients. This implies that TREX1 may have a fundamental role in maintaining the health of small blood vessels that has previously gone unrecognized.

"We're going to be working very hard to understand everything we can about TREX1 to try to give us some hints about what's happening to people with RVCL and how we can help," Atkinson says. "What we learn may provide insights into why these same vessels sometimes start to die off in the elderly, leading to a variety of complications. The disease was discovered here in St. Louis, its genetic basis was identified by the GSC, and now our goal is to find a treatment."

Atkinson's lab has already identified a lead. They were able to show that two of the mutations they identified in RVCL patients create a tailless form of the TREX1 protein that can't properly anchor itself to the part of the cell where it normally does its job. Scientists are currently studying whether this dislocation could have any links to the damage that occurs in RVCL.